PUBLICATION

Regulation of Gluconeogenesis by Aldo-keto-reductase 1a1b in Zebrafish

Authors
Li, X., Schmöhl, F., Qi, H., Bennewitz, K., Tabler, C.T., Poschet, G., Hell, R., Volk, N., Poth, T., Hausser, I., Morgenstern, J., Fleming, T., Nawroth, P.P., Kroll, J.
ID
ZDB-PUB-201201-4
Date
2020
Source
iScience   23: 101763 (Journal)
Registered Authors
Kroll, Jens, Schmöhl, Felix
Keywords
Human Metabolism, Molecular Genetics
MeSH Terms
none
PubMed
33251496 Full text @ iScience
Abstract
Regulation of glucose homeostasis is a fundamental process to maintain blood glucose at a physiological level, and its dysregulation is associated with the development of several metabolic diseases. Here, we report on a zebrafish mutant for Aldo-keto-reductase 1a1b (akr1a1b) as a regulator of gluconeogenesis. Adult akr1a1b-/- mutant zebrafish developed fasting hypoglycemia, which was caused by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) expression as rate-limiting enzyme of gluconeogenesis. Subsequently, glucogenic amino acid glutamate as substrate for gluconeogenesis accumulated in the kidneys, but not in livers, and induced structural and functional pronephros alterations in 48-hpf akr1a1b-/- embryos. Akr1a1b-/- mutants displayed increased nitrosative stress as indicated by increased nitrotyrosine, and increased protein-S-nitrosylation. Inhibition of nitrosative stress using the NO synthase inhibitor L-NAME prevented kidney damage and normalized PEPCK expression in akr1a1b-/- mutants. Thus, the data have identified Akr1a1b as a regulator of gluconeogenesis in zebrafish and thereby controlling glucose homeostasis.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping